Source (MLPCN Center Name): The Scripps Research Institute Molecular Screening Center (SRIMSC)Affiliation: The Scripps Research Institute, TSRIAssay Provider: James D. Potter, University of Miami School of MedicineNetwork: Molecular Library Probe Production Centers Network (MLPCN)Grant Proposal Number 1 R21 NS064821-01Grant Proposal PI: James D. Potter, University of Miami School of MedicineExternal Assay ID: RTF_ACT_SUMMARY

Name: Summary of the probe development efforts to identify activators of the calcium sensitivity of cardiac Regulated Thin Filaments (RTF).

Description:

Cardiomyopathies are myocardial diseases that often lead to cardiac remodeling to compensate for deficiencies in cardiac output (1). Cardiomyopathies are characterized as having systolic dysfunctions (i.e. reduced ejection fraction) in dilated cardiomyopathy or diastolic dysfunctions (i.e. impaired relaxation) in hypertrophic and restrictive cardiomyopathies (2). The regulated thin filament (RTF) is a multi-protein complex responsible for switching cardiac muscle contraction on and off in a calcium dependent manner. Mutations in the genes encoding RTF subunits are often the etiological agents for dilated, hypertrophic and restrictive cardiomyopathies. The RTF is comprised of troponin C (TnC), troponin I (TnI), troponin T (TnT), tropomyosin (Tm) and F-actin. Notably, a hallmark of RTF subunit gene mutations in cardiomyopathies is their ability to alter the calcium sensitivity of cardiac muscle contraction and the morphology of the heart (3). Since multiple forms of cardiomyopathies exist, the identification of new drugs that sensitize (+) or desensitize (-) the calcium sensitivity could potentially reverse these aberrant changes. Moreover, there are no calcium desensitizers in clinical use today. As a result of this HTS campaign, the identification of RTF calcium sensitivity modulators may serve as useful tools for elucidating the roles of these proteins in cardiac muscle contraction and disease (4).

Summary of Probe Development Effort:

This probe development effort is focused on the identification of activators of the calcium sensitivity of cardiac Regulated Thin Filaments (RTF). All AIDs that contain results associated with this project can be found in the "Related Bioassays" section of this Summary AID.